Wednesday, August 20, 2025 8/20/2025

Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer.

Award Number: R37CA272854
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer. - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States with five-year survival after detection is less than 10%. The subset of PDA arises from Intraductal papillary mucinous neoplasm (IPMNs) precursor lesions are distinguished by recurrent activating mutations in GNAS, that encodes G-protein Gαs, and induces cyclic-AMP (cAMP) signaling. GNAS is mutationally activated and amplified pancreatic and many other human tumors, yet its oncogenic functions remain unclear. Therefore, understanding the function of mutant GNAS will provide disease mechanisms and give opportunities to treat PDA even in their early stages. To understand the function of oncogenic GNAS we established a doxycycline-tunable mouse model and showed that mutant GNAS cooperates with oncogenic KRAS to initiate IPMNs that progress to invasive PDA upon p53 loss. GNAS remains critical for the maintenance of established tumors, via a protein kinase A (PKA)-dependent network and resulting inhibition of salt-inducible kinases (SIK1-3). We demonstrated that this network prominently reprograms metabolic pathways which are potential alternative sources of TCA cycle metabolites, respiratory substrates (NADH) and fatty acid intermediates that can support the growth of GNAS mutant tumors. Importantly, GNAS-mutant cancer cells are specifically sensitive to the inhibition of these pathways compared to GNAS-wt tumors. These results establish mutant GNAS as a novel tumor maintenance driver, uncover the underlying PKA-dependent program, establish SIKs as major tumor suppressors, and demonstrate unanticipated metabolic heterogeneity fueling subsets of pancreatic cancer. Based on our published and unpublished supporting data, the overarching goal of this proposal is to understand the roles of critical downstream targets of GNAS-PKA signaling that control the expression of proliferation and metabolic genes. Our research will also illuminate how mutant GNAS regulated expression of a keto dehydrogenase generate biosynthetic and bioenergetic intermediates to support tumor growth. Finally, our study will interrogate the regulation of respiratory activity and its requirement in GNAS mutant pancreatic cancer. This study will leverage advanced methods and unique tools, including global transcriptomic analysis and isotopomer-based metabolic profiling in genetically defined mouse and human organoid systems, preclinical pancreatic cancer animal models, relevant patient-derived xenograft systems and primary samples. Our research will provide understanding of the unique biology of mutant GNAS and points out targetable vulnerabilities in genetic subsets of pancreatic tumors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $370,575 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Biology Research	000	4	8/15/2025	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2024 ( Subtotal = $352,047 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Biology Research	000	3	7/17/2024	NON-COMPETING CONTINUATION	$352,047
														Subtotal = $352,047

Issue Date FY: 2023 ( Subtotal = $363,164 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Biology Research	000	2	7/12/2023	NON-COMPETING CONTINUATION	$363,164
														Subtotal = $363,164

Issue Date FY: 2022 ( Subtotal = $370,575 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Biology Research	001	1	9/13/2022	NEW	$0
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Biology Research	000	1	7/15/2022	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $1,456,361

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Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer.

Award Number: R37CA272854

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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